The present invention relates to dysfunctional energy metabolism of both glucose and lipids in animals and humans. More particularly, a novel combination of metabolic cofactors, L-carnitine combined with acetyl-L-carnitine, restores normal mental and physical activity to aged patients with dysfunctional energy metabolism and, when employed prophylactically, prevents development of related syndromes.
In the normal course of aging an organism's ability to synthesize, conserve, and absorb crucial metabolic cofactors declines. Conversion of nutrients to useful energy within cells involves highly specific enzymatic processes which are sensitive to presence or absence of these cofactors. In the higher order of animals, especially with respect to humans, as well as laboratory rodents, enzyme pathways of energy metabolism are known with relative precision. Despite extensive research efforts, however, interrelationship of many metabolic processes and enzymatic cofactors remain imprecisely known. Indeed, metabolic interrelationships of enzymatic cofactors L-carnitine and acetyl-L-carnitine in cardiac and skeletal muscle have not been completely defined. The same is true in nervous tissue, especially the brain, where available research data concerning function of these cofactors are often contradictory and inconclusive owing to the inordinate difficulty in establishing truly controlled experimental formats. Much of what is known has been gained from the organ's response to traumatic, toxic, and ischemic insults as well as investigations of these cofactors' effects in chronically diseased brains. Such information provides little or no guidance to those concerned with psychophysiologic and psychomotor disturbances or confronting syndromes affecting multiple tissues. The following brief notations are believed to illustrate the complexity of the state of the art knowledge of diseases of energy metabolism.
The study of disease of energy metabolism commonly referred to as mitochondrial diseases is an emerging specialty in human medicine. Most of these diseases arise from mutation of the mitochondrial genomes and, to a lesser extent, nuclear genes. Such mutations result in specific dysfunctional enzymes in metabolic pathways and in structural changes of mitochondria which disrupt enzyme orientation in metabolic pathways thereby impairing their efficiency. Mitochondrial genome mutations may exist at birth but typically occur over time as base dilutions, substitutions, and insertions during the course of replication; or in response to environmental factors, disease, and accumulation of toxic metabolites. Clinical syndromes presented depend upon the metabolic pathway affected and the proportion of dysfunctional mitochondria that has been attained. Organs normally effected by disease of energy metabolism are highly differentiated, nonregenerating tissues requiring high levels of oxygen and energy, such as brain and skeletal and heart muscle. Treatment of these diseases is directed to sustaining life by supplementing high levels of metabolic cofactors in an effort to skew metabolism along specific pathways and to providing substrates for the pathways. Rarely, in human medicine, do deficiencies of cofactors or substrates cause diseases of energy metabolism. In veterinary medicine only a few genetically based diseases of energy metabolism are recognized. Among them are dilated cardiomyopathy in dogs and stress syndrome in swine. However, deficiencies of metabolic cofactors in dogs have been investigated. A study of commonly encountered age-related syndromes in old dogs, examples of which are included in this application, revealed them to be due to dysfunctional energy metabolism. More specially, syndromes involving heart and skeletal muscle were relieved by L-carnitine supplemention while a syndrome affecting the brain was relieved by increased acetyl-L-carnitine intake. However, complex interrelationships exist. For example, a treatment for a psychotic syndrome with acetyl-L-carnitine was successful but resulted in emergence of a heart failure syndrome and both cofactors were required to normalize the dog. In another case, synergistic effects were realized with the two cofactors combined as opposed to their individual use in treating a syndrome involving skeletal muscle. And, in yet another case, a dog that heretofore had required heavy sedation to control an epileptic syndrome, experienced unexpected improvement in after it had been treated with combined L-carnitine and acetyl-L-carnitine for several weeks.
L-carnitine as well as acetyl-L-carnitine are natural constituents of higher organisms, particularly animal heart and muscle tissue and can be synthesized by the body or obtained from red meat, poultry, fish, and dietary products. L-carnitine is absorbed from the small intestine into systemic circulation at a rate of about 2 to 5 mg per pound body weight which is compatible with normal physiologic function and the basis for dosages in the accompanying studies. In standard medical treatment of syndromes related to deficiency of L-carnitine or L-carnitine-dependent enzymes dosage of L-carnitine employed may be 10 to 50 times higher than rate of physiologic intestinal absorption. This affords passive diffusion of carnitine into systemic circulation but such high dosages have the risk of causing diarrhea.
L-carnitine (3-hypodroxy-4-N-trimethylaminobutyric acid) has two main functions, both critical to energy metabolism. The first is translocation of long-chain fatty acids from the cytosol across the outer and inner mitochondrial membranes and intervening space into the mitochondrial matrix. The second function is to modulate intracellular CoA homeostasis within the mitochondrial matrix by transesterifation of acyl-CoA esters produced in B-oxidation which regenerates CoA and acylcarnitine. Accumulation of long chain acyl-CoA esters is a consequence of enzyme disfunction and metabolic impairment or stasis in the B-oxidation system. Resulting shortage of available CoA then limits transfer of acetyl groups to the Krebs cycle for energy production. Acylcarnitine, produced during homeostasis, can be exchanged across the mitochondrial membrane for free carnitine and eventually transported out of the cell to be excreted in urine. Canids are unique in the fact that their liver and kidneys synthesize carnitine but they lack an enzyme in skeletal and cardiac muscle which is crucial to the last stage of L-carnitine synthesis. In dogs L-carnitine is synthesized in the liver and transported to muscle tissue.
Acetyl-L-carnitine (-trimethyl-B-acetylbutyrobetaine) shares intracellular CoA homeostatic function with carnitine. It is the prevalent ester of carnitine in tissue, freely exchangeable across subcellular membranes, and can serve as a pool of acetyl groups to regenerate acetyl-CoA. This property comes into play in instances of excessive exercise where glycolysis has resulted in accumulation of lactic acid in muscle cells. Studies with rat brain tissue show acetyl-L-carnitine to be associated with increased glycolysis and oxygen metabolism. Other studies indicate acetyl-L-carnitine enhances ketone-body metabolism in rat brains. In experimentation with rats acetyl-L-carnitine has been shown to maximize energy production, promote membrane stability, restore membrane changes that are age-related, and serve as precursor to acetylcholine. Cholinergic effects enhance nerve impulse transmission and have been demonstrated to counter or delay age-changes and dementia in brains of rodents and humans.
In addition to depleted available energy and concomitant depression of cell and organ function another consequence of impaired energy metabolism is formation of free oxygen radicals and their destructive effects on proteins and other large molecules, mitochondrial membranes, and especially mitochondrial DNA. Environmental sources of free radicals are infection, drugs, hypoxia, chemicals, and food. These destructive effects are cumulative leading to development of physiologic dysfunctions with increasing age, and along with mitochondrial genome mutation from other causes, must be considered as contributors to the etiology of syndromes seen with the dogs in this report. Normally, cell and organ function deteriorates with age resulting in reduced biosynthesis of metabolites and cofactors, reduced digestive function and enteral absorption, and impaired renal tubule resorption from glomerular filtrate. In elderly dogs any or all of the above can lead to depletion of tissue reserves of L-carnitine and acetyl-L-carnitine to the extent that energy metabolism is impaired.
Four syndromes, psychosis, skeletal muscle weakness and atrophy, epileptiform convulsions, and cardiomyopathy were observed in dogs in this study. Syndromes presented as singular entities as in the skeletal muscle syndrome or as complex of syndromes. Psychosis, in the form of extreme anxiety with trembling, hiding and panicky flight are common in old dogs exposed to sharp noises such as fireworks discharges. Even a mild stimulant such as the sound of cellophane being crumbed into a ball will illicit a panic response in some dogs. Management of most such cases is with tranquilizers during periods when stimuli are most prevalent (e.g. New Years Eve and The Fourth of July). Tranquilizers do nothing to cure the patient, their effect is psychological depression. When patients become extremely debilitated by the psychosis mood altering drugs such as doxepin and fluoxetine can be employed. Here again a cure will not be forth coming. At best the animal will be so heavily sedated as to not pose a threat to itself, property, or the public. Pharmacologically-active mind-depressions do not correct any metabolic imbalances in the brain, hence do not effect a cure. In some cases psychotic episodes progress to grand mal seizures. Depressant drugs are the common means employed for their control. Phenobarbital, primidone, and/or KBr are consumed once to several times a day. The drugs do not correct the underlying metabolic dysfunction in the brain but they do stop the seizures at the expense of greatly depressing the patient. Psychotic and seizuring dogs are not demented in the sense that there is large-seal neuronal dysfunction with loss of inelegance, memory, or awareness of surroundings. Psychoses are almost the opposite, with heightened awareness of sounds and events in the environment. They may precipitate seizures.
Among the causes of skeletal muscle weakness and reduction of mass are nutritional deficiency, in particular deficiency of SE and vitamin E. In cases of nutritional myopathy, refined to as white muscle disease, the vitamin E interrelates metabolically with SE and can be a valuable adjust to therapy. This condition is common to herbivorous and omnivorous but not carnivorous. A myopathy common in dogs is denervation myopathy, a condition that develops secondary to herniation of intervertebral dises and ankylosing spondyloarthropathy. Where spinal nerves are damaged reduced impulse stimulation to the innervated muscle leads to weakness, degeneration, and atrophy. This form of muscle disease is managed by attempting to reduce trauma to the spinal nerve by controlling chronic inflammation and bone formation along the nerve's course from the spine with drugs classified as non-steroidal anti-inflammatory agents. If skeletal muscle is not exercised it will become weak and degenerate and eventually atrophy. This condition, common to traumatic injuries, precludes normal function after extended periods of time. There are auto-immune myopathies where the body produces an immune reaction, usually to some infectious agent, that cross reacts with skeletal muscle. Management of these conditions is based upon suppression of the immune reaction for an undetermined period of time. Eventually, the reaction subsides and the immune depressant drugs can be with drawn. There are other causes of skeletal muscle weakness and atrophy. Clinically they are morphologically similar to one and other and require biopsy for definitive diagnosis.
Heart failure secondary to dilated cardiomyopathy has been treated with high dosages of L-carnitine, 100 mg per pound body weight. Such massive therapy is only moderately successful, at best. In most cases prognosis is very guarded. One reason for the poor response may be that diagnosis is not forthcoming until pathology is so advanced it cannot be reversed. Another consideration is that L-carnitine therapy only addresses lipid metabolism in the heart ignoring the part glycolysis may contribute. Cardiac arrhythmias are part of heart failure and evidence of pathology of heart muscle. Arrhythmias are treated with pharmachologically active drugs which may stabilize the heart. Drugs such as lidocaine, propanalol, digoxin, and procainamide all are useful in stabilizing the heart beat which may be critical at times but such drugs do not address the metabolic disturbance that caused the pathology. It is common for dogs with cardiac arrhythmias to die suddenly or, at best, be forced to remain on medication for extended periods, even for life.
As a consequence of above-noted complexities in identifying and treating syndromes related to dysfunctional energy metabolism as well as understanding their interrelationships little progress has been achieved in prevention and therapy. The following examples of U.S. Patents relating to carnitine and acetyl-L-carnitine are illustrative of the existing state of the art.
U.S. Pat. No. 4,346,107 relates specifically to the use of acylcarnitine in treating dementia of human patients particularly when mental dysfunction is related to impaired cerebral blood flow. Typifying numerous approaches to management of dementias, is does not investigate psychoses and epileptiform seizures as being associated with deficits of energy metabolism, their connection with deficiencies of L-carnitine and acetyl-1-carnitine, the possibility of precipitating other energy deficit syndromes as a consequence of therapy with a single metabolic cofactor, and the need for therapy that modulates both glycolyses and lipid metabolism.
U.S. Pat. No. 4,599,232 relates to combination of carnitine or acetylcarnitine and coenzye Q10 for tissue metabolic disorders involving circulatory function. The patent's use of coenzymes Q10 directs its effects towards control of free radical excess and facilitation of oxidative phosphorylation, the final stage of energy metabolism. It does not address the observed synergistic effects of combined L-carnitine and acetyl-L-carnitine on glycolysis and lipid metabolism nor does it recognize the need of both metabolic cofactors when treating dysfunctional energy metabolism related to deficit of L-carnitine or acetyl-L-carnitine as discovered in the present patent.
U.S. Pat. No. 5,576,384 relates to the general use of acylcarnitine for therapy of patients with Acylcarnitine Metabolic Dysfunction Syndrome. It excludes consideration of carnitine metabolism disorders and the combined therapy for disorders where both deficiencies may exist.
Following are references pertaining to diseases of energy metabolism their causes and treatments.
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